This program project is an interdisciplinary effort to broaden our understanding of the roles that eicosanoids and hemostatic factors play in the pathogenesis of cerebrovascular thrombosis and to enhance our knowledge concerning the use of pharmacological agents and gene transfer for prevention of arterial diseases and stroke. Our major goal is to bring the basic investigations into clinical applications in improved care of patients with stroke and allied disorders. Substantial progresses have been made during the previous period. These progresses have led to the proposal of new specific aims. This renewal application consists of four interrelated projects and one core unit. Wu's project aims at understanding the regulation at molecular level of key enzymes that catalyze the biosynthesis of thromboxane A and prostacyclin. It focuses on elucidating the mechanism by which cytokines and growth factors induce prostaglandin H synthases and salicylates suppress their expression. Kulmacz's project aims at mapping the topology of thromboxane synthase and determining the structure-function relation of this enzyme. McIntyre and Hellum project study the expression of hemostatic factors under shear stress. Core B laboratory procedure development and standardization as well as reagent preparation. Thus, the scope of the program ranges from molecular and cell biology to clinical patient investigations, and there exists an exciting potential for a rapid application of basic information to clinical management of stroke and vice versa. The program involves professional personnel with a long record of interests in stroke research who have different but complementary backgrounds and expertise in hematology, hemostasis and thrombosis, neurobiology, cell and molecular biology, neurology, biochemistry, pharmacology, tissue culture, enzymology and analytical chemistry. It is intended that this program will enable several laboratories to work individually and together to achieve the highest degree of innovation and productivity.